This proposal describes theoretical ways to relate structural features of ion channel proteins and of their phospholipid environment to channel behavior, stressing problems central to excitable cell physiology. Model calculations clarifying issues in permeation and selectivity are described. An improved approach to simulation, constructing force fields reliable in channel environments, is described. A new way to treat lipid influences on channels is outlined. Calculations of free energy profiles, based on an exact, computationally efficient way to treat a limited number of molecular features of the ion(s), water and protein charges that surround and form the aqueous pore, are proposed and used to understand and interpret major structural features of the selectivity domain of potassium channels: Why is it multiply occupied? Why does it reject small alkali cations? Why is the bridge water loosely coordinated? The method is applied to crystalline gramicidin conformers to determine why some favor anion occupancy. As more channel structural data (on nicotinic receptor and voltage gated cation families) become available, their selectivity and permeation characteristics will be investigated. Ways to meld these exact techniques with standard simulational methods are described. An application that may disentangle the enthalpic from the entropic influences on the permeation kinetics of the model potassium channel is presented. A new way to construct water-water and ion-water force fields is outlined. This approach, by accurately treating short-range structural forces and intermediate range electrostatics, is designed to yield force fields reliable over a wide range of thermodynamic phase space. Water and hydrated species in channels and in bulk water are very different structurally. Reliable simulational methods must account for these differences. The new force fields, being valid over extended p-V-T domains, answer this need. Channel formation is greatly influenced by interaction with the membrane. The crucial interactions correlate surface displacements in membrane regions about a bilayer width apart. At such short separations elastic behavior becomes cooperative. A new electroelastic theory of membranes is outlined and used to study peptide insertion energetics.